4193 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with poor outcomes in advanced disease. Nesuparib is a dual tankyrase (TNKS) and poly(ADP-ribose) polymerase (PARP) inhibitor that induces a “BRCAness” phenotype via WNT and Hippo signaling. This Phase Ib study evaluated the safety, tolerability, and preliminary antitumor activity of nesuparib combined with standard first-line chemotherapy in patients with locally advanced or metastatic PDAC. Methods: This multicenter, open-label, Phase Ib dose-finding study evaluated oral nesuparib plus GemAbraxane or mFOLFIRINOX in advanced PDAC. Nesuparib was administered orally using a 3+3 dose-escalation design with intermittent schedules, including DL1 (25 mg, 5 days on/2 days off), DL-1 (12.5 mg, 5 days on/2 days off), and DL-2 (12.5 mg, 3 days on/4 days off). Primary objectives were to assess safety and determine the maximum tolerated dose and recommended Phase II dose. Secondary objectives included preliminary efficacy. Results: As of December 31, 2025, 27 patients were enrolled and treated (GemAbraxane, n = 14; mFOLFIRINOX, n = 13). Most patients had metastatic disease. In the GemAbraxane arm, acceptable tolerability was confirmed at DL-1 and DL-2, whereas tolerability was not established in the mFOLFIRINOX arm. Across both treatment arms, grade 3/4 AEs were mainly hematologic toxicities. Rates of anemia, thrombocytopenia, and neutropenia were 57.1%, 64.3%, and 92.9% in the GemAbraxane arm, compared with 84.6%, 92.3%, and 84.6% in the mFOLFIRINOX arm, respectively. No treatment-related deaths occurred, and most AEs were manageable with standard supportive measures. Non-hematologic AEs were mostly low-grade and manageable. In the GemAbraxane arm, the objective response rate (ORR) and disease control rate (DCR) were 53.8% and 92.3%, respectively, including one patient with a complete response (CR) of the target lesion and overall survival exceeding 3 years. Median progression-free survival (mPFS) was not reached, and median overall survival (mOS) was 14.2 months (data immature and follow-up is ongoing). In the mFOLFIRINOX arm, the ORR was 38.5% with a DCR of 92.3%, while mPFS and mOS were 7.33 and 18.5 months, respectively. Conclusions: Nesuparib combined with GemAbraxane demonstrated acceptable tolerability and encouraging antitumor activity in advanced PDAC. These findings support further evaluation of nesuparib using a 12.5 mg intermittent dosing schedule in the first-line treatment setting; a Phase II trial is currently ongoing. Clinical trial information: NCT05257993 . Outcome Nesuparib + GemAbraxane (n=13) Nesuparib + FOLFIRINOX(n=13) PR 7 (53.8%) 5 (38.5%) SD 5 (38.5%) 7 (53.8%) PD 1 (7.7%) 1 (7.7%) ORR 53.8% 38.5% DCR 92.3% 92.3% mOS 14.20 mo (data immature) 18.50 mo mPFS Not reached 7.33 mo
Choi et al. (Wed,) studied this question.